1) Neonatal tolerance. Female mice can be primed by male dendritic cells or tolerized by male spleen cells up to day 24 after birth. Thus neonates are not especially tolerizable. They can be immunized by professional APCs as long as the inoclum does not contain a large proportion of non-APC cells. 2) Maternal tolerance. Using quantitative PCR for the Y chromosome we occasionally find male cells in the organs of pregnant mice. This traffic is very sporadic however and we conclude that it is unlikely to be a major mechanism by which the fetus alters the mother's immune response. 3) Results of tolerance in Tg mice. To test which haplotypes support the development of a Tg TCR derived from an F1 mouse, we created T cell clones from F1 mice, isolated the genes for their antigen specific receptors and generated Tg mice. The first two transgenics are now being bred to create the appropriate test animals. Two more are on the way. THE THYMIC STEM CELL - is it precommitted? Frequency estimates indicate that each 11 day fetal thymus lobe contains a single CFUS stem cell. Thus there are uncommitted stem cells in the early fetal thymus. T CELL MEMORY - We are studying killer cell memory in mice depleted of T helper cells. Preliminary results suggest that killer cell memory lasts at least 3 months in the absence of T helper cells. NEW THIS YEAR. Two major theories, one on memory and one on the fundamental "raison d'etre" of the immune system. On Memory: Both short and long term memory are maintained by re- stimulation of memory cells: short term memory by antigen retained by Follicular Dendritic cells and long-term memory by cross- reactive environmental antigens or by re- infection with the original pathogen. The immune system recognizes "danger" not "non-self": "Danger" is defined by the immune system as cell stress or non-apoptotic death, eg. lysis caused by a cut or a viral infection. This activates local antigen presenting cells (APCs) which take captured antigens to the nearest lymph node and present them to passing T cells. immune responses are only initiated when abnormal death activates APCs. T cells able to see the normal surface MAP of APCs are deleted in the thymus and any T cells able to see other bodily tissues are deleted in the periphery. This peripheral deletion occurs because resting T cells are programmed to die if they bind antigen unless they receive a special APC-derived activating signals. Thus any T cell specific for a peripheral (non-APC) tissue dies when it binds to that tissue. This view of the immune system explains many phenomena that the old self-non-self view does not and it offers several new strategies for the treatment of tumors and for successful organ transplantation.